Cigarette smoking is a leading cause of cancer as well as cardiovascular and respiratory disease and is the leading preventable cause of death in the United States. Many factors contribute to cigarette smoking, including nicotine, other chemicals in tobacco smoke, and conditioned reinforcers. This R01 proposal focuses on the crucial role that nicotine plays in mediating the abuse and dependence liability of nicotine, and focuses on nicotine receptor mechanisms mediating the behavioral effects of currently prescribed medications for smoking cessation including nicotine (patch and gum), varenicline (low efficacy nicotine agonist), and bupropion (catecholamine reuptake inhibitor and nicotine antagonist). Drug discrimination will be used to examine nicotine receptor subtypes and pharmacologic (agonist) efficacy at nicotine receptors and their contribution to the behavioral effects of nicotine receptor ligands. A novel drug discrimination procedure will be developed to index nicotine withdrawal and the procedure will be evaluated for its pre-clinical utility as an index of medication effectiveness. Aim 1 tests the hypothesis that the same 22-containing nicotine receptors, specifically 1422 receptors, mediate the effects of nicotine, varenicline, and cytisine, as evidenced by similar antagonism with nicotine antagonists (DH2E). Aim 2 tests the hypothesis that varenicline and cytisine have lower agonist efficacy than nicotine in vivo. Experimental support for the hypothesis of Aim 2 will include greater loss of sensitivity (cross-tolerance) to varenicline and cytisine than tolerance to nicotine in nicotine-treated monkeys, failure of varenicline and cytisine to substitute for a relatively large dose of nicotine, and substitution of varenicline and cytisine for the discriminative stimulus effects of a nicotine antagonist in nicotine-dependent monkeys. Aim 3 tests the hypothesis that discriminative stimulus effects are more sensitive to nicotine withdrawal than directly observable signs. Nicotine and other currently available pharmacotherapies are expected to attenuate more effectively the discriminative stimulus effects of nicotine withdrawal as compared to signs of withdrawal. Although currently available pharmacotherapies for smoking cessation are effective, there is considerable margin for improvement. These pre-clinical studies will help identify pharmacologic dimensions upon which to develop novel medications that could further reduce the devastating consequences of cigarette smoking.